We included only RCTs, irrespective of language, blinding, or publication status, in participants with very early- or early-stage
hepatocellular carcinoma, irrespective of the presence of
cirrhosis,
portal hypertension, aetiology of
hepatocellular carcinoma, size and number of the tumours, and future remnant liver volume. We excluded trials including participants who were previously liver transplanted. We considered interventions compared with each other,
sham, or no intervention.
DATA COLLECTION AND ANALYSIS: We calculated the odds ratio, mean difference, rate ratio, or hazard ratio with 95% confidence intervals using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed the risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis using Stata, and the quality of the evidence using GRADE.
MAIN RESULTS: Eighteen trials met the inclusion criteria for this review. Four trials (593 participants; 574 participants included for one or more analyses) compared surgery versus
radiofrequency ablation in people with early
hepatocellular carcinoma, eligible to undergo surgery. Fourteen trials (2533 participants; 2494 participants included for various analyses) compared different non-surgical interventions in people with early
hepatocellular carcinoma, not eligible to undergo surgery. Overall, the quality of evidence was low or very low for all outcomes for both comparisons. Surgery versus radiofrequency ablationThe majority of participants had cirrhotic livers, and the
hepatocellular carcinoma was of viral aetiology. The trials did not report the participants'
portal hypertension status or whether they received adjuvant
antiviral treatment or adjuvant
immunotherapy. The average follow-up ranged from 29 months to 42 months (3 trials).There was no evidence of a difference in all-cause mortality at maximal follow-up for surgery versus
radiofrequency ablation (hazard ratio 0.80, 95% confidence interval (CI) 0.60 to 1.08; 574 participants; 4 trials; I2 = 68).
Cancer-related mortality was lower in the surgery group (20/115 (17.4%)) than in the
radiofrequency ablation group (43/115 (37.4%)) (odds ratio 0.35, 95% CI 0.19 to 0.65; 230 participants; 1 trial). Serious adverse events (number of participants) was higher in the surgery group (14/60 (23.3%)) than in the
radiofrequency ablation group (1/60 (1.7%)) (odds ratio 17.96, 95% CI 2.28 to 141.60; 120 participants; 1 trial). The number of serious adverse events was higher in the surgery group (adjusted rate 11.3 events per 100 participants) than in the
radiofrequency ablation group (3/186 (1.6 events per 100 participants)) (rate ratio 7.02, 95% CI 2.29 to 21.46; 391 participants; 2 trials; I2 = 0%). None of the trials reported health-related quality of life. One trial was funded by a party with vested interests; three trials were funded by parties without any vested. Non-surgical interventionsThe majority of participants had cirrhotic livers, and the
hepatocellular carcinoma was of viral aetiology. Most trials did not report the
portal hypertension status of the participants, and none of the trials reported whether the participants received adjuvant
antiviral treatment or adjuvant
immunotherapy. The average follow-up ranged from 6 months to 37 months (11 trials). Trial participants, who were not eligible for surgery, were treated with
radiofrequency ablation,
laser ablation, microwave ablation, percutaneous
acetic acid injection, percutaneous alcohol injection, a combination of
radiofrequency ablation with systemic
chemotherapy, a combination of
radiofrequency ablation with percutaneous alcohol injection, a combination of transarterial chemoembolisation with percutaneous alcohol injection, or a combination of transarterial chemoembolisation with
radiofrequency ablation.The mortality at maximal follow-up was higher in the percutaneous
acetic acid injection (hazard ratio 1.77, 95% CI 1.12 to 2.79; 125 participants; 1 trial) and percutaneous alcohol injection (hazard ratio 1.49, 95% CI 1.18 to 1.88; 882 participants; 5 trials; I2 = 57%) groups compared with the
radiofrequency ablation group. There was no evidence of a difference in all-cause mortality at maximal follow-up for any of the other comparisons. The proportion of people with
cancer-related mortality at maximal follow-up was higher in the percutaneous alcohol injection group (adjusted proportion 16.8%) compared with the
radiofrequency ablation group (20/232 (8.6%)) (odds ratio 2.18, 95% CI 1.22 to 3.89; 458 participants; 3 trials; I2 = 0%). There was no evidence of a difference in any of the comparisons that reported serious adverse events (number of participants or number of events). None of the trials reported health-related quality of life. Five trials were funded by parties without any vested interest; the source of funding was not available in the remaining trials.
AUTHORS' CONCLUSIONS: The evidence was of low or very low quality. There was no evidence of a difference in all-cause mortality at maximal follow-up between surgery and
radiofrequency ablation in people eligible for surgery. All-cause mortality at maximal follow-up was higher with percutaneous
acetic acid injection and percutaneous alcohol injection than with
radiofrequency ablation in people not eligible for surgery. There was no evidence of a difference in all-cause mortality at maximal follow-up for the other comparisons. High-quality RCTs designed to assess clinically important differences in all-cause mortality and health-related quality of life, and having an adequate follow-up period (approximately five years) are needed.